Human and veterinarian medical and surgical procedures often require the use of various materials and substrates that can be used as implants, scaffolding for tissue growth or repair, wound closures, adhesives or glues, or as delivery mechanisms to deliver genes or drugs to a specific site for localised therapy. The materials should be biologically inert, so as not to react with surrounding tissue. It is also important that the materials are sufficiently strong to perform the required function in the patient's body, while at the same time being relatively flexible.
While the materials or substrates that are to be used as surgical implants or delivery devices are specifically designed for each particular use, such materials tend to have common disadvantages or drawbacks. Materials used for wound closures, stents, or as devices to deliver therapeutic compounds or genes tend to be synthesised from synthetic polymers. Such polymers often are not biodegradable, necessitating either a second procedure to remove the implanted material, or that the material be left permanently in place. Furthermore, due to their synthetic nature, such materials are not fully compatible with the body. That is, there is a risk that the patient may develop an inflammatory or immunological reaction to the implanted material.
As a result, biodegradable polymers have been developed for surgical use and implantation. These include polylactic acid (Kulkarni et al, 1966), polyanhydrides and polyorthoesters (Domb et al, 1989), polyamino acids (Miyake et al, 1974), and polyesters of alpha-hydroxy acids (Holland et al, 1986). U.S. Pat. No. 4,957,774 discloses the cross-linking of hyaluronic acid to produce a biodegradable, swellable plastic polymer. U.S. Pat. No. 4,741,337 discloses a biodegradable, glycolide-rich polymer for use as a wound fastener.
Recent attempts to produce synthetic polymers for use in surgical implants have involved polymers that are more inert and therefore are more capable of interfacing with living tissue in a non-reactive manner. U.S. Pat. No. 4,526,938 discloses the preparation of a synthetic, amphipathic polymer incorporating a therapeutically active peptide that is released upon breakdown of the polymer. The hydrophilic portion of the polymer may not be fully biodegradable. U.S. Pat. No. 4,716,203 discloses the preparation of a synthetic, degradable, water-soluble, thermoplastic block copolymer containing polyglycolic acid and polyethylene glycol. This polymer can be formed into a hydrogel for use as implant material. U.S. Pat. No. 5,162,430 discloses the preparation of a semi-synthetic polymer by cross-linking collagen, a biological polymer, to synthetic hydrophilic polymers such as polyethylene glycol. Semi-synthetic polymers are also disclosed in U.S. Pat. No. 5,324,775, which describes the covalent attachment of biological polymers such as polysaccharides to polyethylene glycol polymers.
These synthetic or semi-synthetic polymers are partially or fully biodegradable, which allows for at least limited dissolution of the implanted material. However, the degradation products may be toxic to surrounding tissue at higher concentrations, and rapid breakdown can lead to harmful localised levels of degradation product. As well, inflammation and cytotoxicity are not fully eliminated with the use of these polymers. Furthermore, the preparation of these polymers requires the use of organic solvents for polymerisation. These solvents are expensive and can be toxic, mutagenic or carcinogenic to tissue at the implant site, as well having a potentially denaturing effect on proteins or drug compounds that may also be delivered to the implant site. Additionally, this requirement for organic solvents to facilitate polymerisation means that these polymers cannot polymerise in vivo.
In order to avoid the problems encountered with synthetic or semi-synthetic polymers, materials derived from biological substances have also been described. EPA 0068149 discloses a web-like material prepared from fibrin and fibrinogen that can be used as a wound covering, bone filler or as a delivery system for therapeutically active compounds. This polymer, while being fully biologically-derived, has the disadvantage of being too rigid, even when in contact with water or biological fluids. This rigidity significantly limits the applications for which this material can be used. German Patent No. 3,214,337 describes a multi-layered sheet material that is composed of glycoprotein layers containing alternatively thrombin or fibrinogen. This separate layering of the thrombin and fibrinogen results in a weaker material, as a cross-linked fibrin web is not generated. EPA 0485210 discloses a collagen membrane that contains fibrin. However, animal-derived collagen can elicit a strong inflammatory response from some patients. Currently, transgenic or recombinant human collagens are extremely expensive to produce.
Surgical techniques often involve the use of adhesives to join severed tissue or bone and to adhere tissue grafts at a surgical site. Conventional techniques involve the use of synthetic glues such as cyanoacrylates. However, these glues are not readily biodegraded, and tend to form an inflexible and relatively weak bond. U.S. Pat. No. 5,643,192 describes fibrin-based materials that are used to form stronger bonds when used as bioglues, and are more readily biodegraded. Fibrin has been shown to support keratinocyte and fibroblast growth at the implant site. However, as with the cyanoacrylates, the fibrin-based materials are not stretchable when polymerised. This lack of elasticity leads to a high rupture-rate for seals formed with these materials, especially when the bonds formed are subject to deformation stress. Other adhesives that use the plasma protein serum albumin together with a multifunctional aldehyde have been developed. These adhesives provide a strong bond, but carry the risk of infection due to the biological source of the blood protein. As well, many of the adhesives currently in use as bioglues tend to cause inflammation at the surgical site due to the high concentration of cross-linking agents they contain.
U.S. Pat. No. 5,498,259 discloses a method of fusing bone by chemically removing a thin layer of the mineral matrix from the surfaces of bone to be joined and then painting the joint with a fluorescent dye and heating the dye using electromagnetic radiation to seal the joint. This process is not suitable for clinical use as it is not performed in an in vivo setting. As well, the strength of the bond is not sufficient for clinical applications.
Various materials are also used in surgical techniques to fill bone cavities, or to replace some or all of an existing bone. One current technique involves the use of polypropylene fumarate (“PPF”) as a cross-linked bone replacement matrix. PPF cross-links at low temperatures, possesses high mechanical strength and biodegrades into non-toxic degradation products, making it a suitable material for bone replacement, scaffolding and cement. However, formulations of PPF that incorporate toxic monomers in the PPF polymer, such as a vinyl monomer or N-vinyl pyrrolidine, can result in delivery of toxic impurities to the surgical site if the matrix is not completely polymerised, as well the release of toxic degradation products upon biodegradation.
Another use of material in medical procedures is as a delivery system for therapeutic products such as DNA, drugs or cells. Material containing the therapeutic product is often coated on surgical implants. Fibrin glue has been used to deliver cultured cells and exogenous growth factors (Currie et al). Fibrin glue may not be ideal for the prevention of restenosis, or renarrowing of blood vessels after surgery, as the presence of residual thrombin in the fibrin glue may induce thrombosis, which may lead to vascular obstruction at the implant site. U.S. Pat. No. 5,83,651 describes the use of fibrin glue coated on stent implants as a method of delivering therapeutic virus.
Various mechanical devices have also been used to deliver therapeutic products to a particular site in the body. Stents that release naked DNA that encodes therapeutic gene products have been used, but this method results in a low rate of transduction of surrounding cells with the therapeutic DNA, as well as transient expression of the therapeutic gene (Klugherz et al). Another approach involves the use of balloon catheters that contain micro-encapsulated spheres of the therapeutic product, as disclosed in U.S. Pat. Nos. 6,129,705 and 6,159,946. This approach has the disadvantage of the balloon catheter causing occlusion of blood flow for considerable lengths of time, creating risk to the patient. U.S. Pat. No. 6,197,013 discloses the use of micropourous metal microneedles that have been coated directly with the therapeutic product to deliver the product into the wall of a blood vessel. The efficacy and safety of the system is yet to be proved comprehensively.
In summary, there is a general need for a material that can be used for various medical and surgical applications that is preferably biodegradable, biologically inert, biocompatible and immunocompatible, and has significantly reduced toxicity. Such a material should ideally be able to rapidly polymerise in situ, be capable of connecting and stabilising tissue in a moist environment and be able to retain strength and flexibility when used as an adhesive or when implanted in a patient. It is also important that the material does not impede proper regeneration of tissue at the implant site.